Beta glycosphingolipids suppress rank expression and inhibit natural killer T cell and CD8+ accumulation in alleviating aortic valve calcification.

CD8 lymphocytes play a role in aortic valve inflammation leading to aortic valve calcification (AVC). RANK is a transmembrane protein that is important in osteoclast differentiation and calcification. Beta-glucosylceramide (beta-GC) together with beta-lactosylceramide (beta-LC), the 1:1 combination of beta- glucosylceramide and beta-lactosylceramide, designated IGL, exerts an immune modulatory effect in various inflammatory disorders in a CD8- and NKT (natural killer T cell)-dependent manner. We hypothesized that IGL may affect the inflammatory condition associated with AVC. AVC was induced in rats by oral administration of a high-adenine, high-phosphorus diet and was assessed by multislice computer tomography. Administration of this diet was associated with a marked increase in CD8 and NKT lymphocyte accumulation in the aortic valve. Administration of IGL led to marked suppression of RANK expression, associated with inhibition of both NKT and CD8 lymphocyte accumulation in the aortic valve. These effects were associated with a significant improvement in the degree of AVC in IGL-treated animals (25 and 53 by Agatston Score, in IGL-treated and controls, respectively). CD8 and NKT lymphocytes play a role in the pathogenesis of AVC, and RANK-mediated NKT inhibition by beta-glycosphingolipids can alleviate AVC.

The discrete and combined effect of SREBP-2 and SCAP isoforms in the control of plasma lipids among familial hypercholesterolaemia patients.

BACKGROUND AND AIM: Hypercholesterolaemia is a major risk factor for atherosclerosis. Cholesterol is modulated by genetic and environmental factors. An important regulatory pathway is controlled by the sterol-regulatory element-binding proteins (SREBPs) and the SREBP cleavage-activating protein (SCAP). Both SREBP-2 and SCAP are candidates to contribute to the development of atherosclerosis. We investigated the possible effects of the variability of proteins involved in this regulatory pathway on plasma lipids among familial hypercholesterolaemia patients. METHODS AND RESULTS: Single nucleotide polymorphisms (SNPs) in the genes encoding SREBP-2 and SCAP causing amino acid changes at positions 595 (595G/A) and 796 (796I/V), respectively, were genotyped in 801 FH individuals originating from Israel, The Netherlands, and Switzerland. A linear regression model to examine the associations between SREBP-2 and SCAP isoforms and lipid and lipoprotein levels was used. In females, homozygosity either for the SREBP-2-595A or for the SCAP-796I isoform was associated with higher LDL-cholesterol plasma concentrations (14.7 mg/dl and 20.3 mg/dl, respectively). Surprisingly, heterozygosity for the combination SREBP-2-595A/SCAP-796I was associated with a decrease of 30.28 mg/dl in LDL-C (p-value for gene-gene interaction=0.09). No such effect was observed among FH males. Subgroup analysis considering the most frequent (N>/=24) LDL receptor mutations (del191-2, ins313+1-2, C660X, E207K, S285L) revealed further gene-dosage- and gender-dependent effects of the SCAP mutations on LDL-cholesterol concentrations (p=0.0345). These effects were, however, not present when less frequent LDL receptor mutations were investigated. CONCLUSIONS: These results suggest a possible gene-gene interaction between the genes encoding SREBP-2 and SCAP that modulate plasma lipids in a strictly gender-specific fashion. Further investigation is needed to confirm this effect. A study in a larger FH group or in non-FH hypercholesterolaemic subjects may further define the role of this regulatory mechanism in determining plasma lipid concentration.

The value of cine nuclear magnetic resonance imaging for assessing regional ventricular function.

Previous nuclear magnetic resonance (NMR) imaging studies to assess left ventricular function have used multiple axial planes, which are compromised by partial volume effects and are time consuming to acquire and analyze. Accordingly, an imaging approach using cine NMR and planes aligned with the true cardiac axes of the left ventricle was developed in views comparable with left ventricular cineangiography. Cine NMR imaging was used to assess regional wall motion and was validated by comparison with biplane left ventricular cineangiography. Fifty-nine patients underwent cineangiographic and NMR studies within 72 h. A poor quality NMR study precluded analysis in 4. leaving a study group of 55 patients (mean age 58 +/- 12: 17 women). Cine NMR movie loops were acquired in two long-axis planes: 1) right anterior oblique plane, parallel to the septum, and 2) four chamber orthogonal plane, perpendicular to the septum (this view is comparable to the angiographic left anterior oblique view). To assess regional wall motion, the left ventricle in both cine NMR and cineangiographic images was divided into five segments and graded on a five point grading scale from 3 for normal through 0 for akinesia and -1 for dyskinesia. Regional wall thickening was used qualitatively to aid in the analysis of wall motion. For the 275 segments compared in the right anterior oblique view, agreement was within one grade in 263 (95.6%) of 275 segments, whereas absolute agreement was observed in 171 (62%) of 275 segments. In the left anterior oblique view, of 200 segments evaluated, agreement within one grade was achieved in 184 segments (92%) and agreement was complete in 132 (66%).(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term angiographic follow-up of coronary balloon angioplasty in patients with diabetes mellitus: a clue to the explanation of the results of the BARI study. Balloon Angioplasty Revascularization Investigation.

OBJECTIVES: We sought to compare the angiographic outcome of diabetic patients (treated with insulin or oral hypoglycemic agents) after successful coronary angioplasty with that in nondiabetic patients. The analysis included the outcome of the dilated (restenosis) and nondilated narrowings (disease progression). BACKGROUND: Recent data have confirmed that diabetes mellitus is an important risk factor for long-term adverse events. These adverse events are more common after balloon angioplasty than after bypass surgery (Bypass Angioplasty Revascularization Investigation [BARI]). METHODS: We examined retrospectively 353 coronary angiograms of 248 patients (55 diabetic, 193 nondiabetic) who were referred for diagnostic angiography >1 month after successful angioplasty (1.4 +/- 0.6 [mean +/- SD] repeat angiograms/patient). Restenosis and disease progression/regression were compared between groups by means of quantitative angiography. RESULTS: Baseline clinical and angiographic characteristics were similar in both groups. There was a nonsignificant trend for a higher restenosis rate of dilated narrowings in diabetic patients. There were no significant changes between diabetic and nondiabetic patients in the rates of progression and regression of narrowings that were not dilated during the initial angioplasty. The main difference was in the rate of appearance of new narrowings: There was a 22% increase in the number of narrowings on the follow-up angiogram in diabetic patients (38 new, 174 preexisting narrowings) compared with 12% (86 new, 734 preexisting narrowings) in nondiabetic patients (p < 0.004). Diabetes mellitus and the performance of angioplasty in the artery had an additive risk for development of new narrowings, which were identified in 15 (16.9%) of 89 arteries with and 16 (13.2%) of 121 without angioplasty in diabetic patients and in 42 (12.7%) of 331 arteries with and 38 (7.3%) of 518 without angioplasty in nondiabetic patients (p = 0.009). CONCLUSIONS: The combination of diabetes mellitus and an artery that was instrumented during balloon angioplasty is additive and increases the risk of formation of new narrowing in that artery. This finding may explain the high adverse event rates observed in diabetic patients in the angioplasty arm of the BARI study, most of whom had angioplasty performed in at least two arteries.

Early treatment of acute myocardial infarction with intravenous streptokinase. A high-risk syndrome.

Fifty-one successive patients treated with intravenous streptokinase 1.7 +/- 0.8 (mean +/- SD) hours after onset of symptoms of acute myocardial infarction were evaluated during a three-month posthospital follow-up period. Coronary angiography was performed four to nine days after the initial hospital admission. Twenty-eight patients had a second late angiogram. Forty-one patients had successful reperfusion but only 25% of all patients were without significant clinical cardiovascular manifestations during this period. Postmyocardial infarction angina pectoris occurred in 21 patients, an abnormal stress test result was present in 28 patients, eight patients developed congestive heart failure, and five patients had reinfarction. An intervention with percutaneous transluminal coronary angioplasty or coronary artery bypass graft was performed in 15 (37%) of 41 reperfused patients. A significantly higher intervention rate was present in patients treated with streptokinase within one hour following the onset of symptoms. Early reocclusion (within three months of the infarct) was noted in patients with 60% or more residual stenosis in their infarct-related coronary artery. These patients also had a significantly greater incidence of angina pectoris. Our findings indicate that early thrombolytic therapy of acute myocardial infarction preserves myocardium, and since the infarct-related artery is patent, but narrowed, the jeopardized area is responsible for a high-risk syndrome with an increased likelihood of ischemic symptoms. An early aggressive approach may be indicated, especially for patients with greater than 60% residual stenosis in their infarct-related coronary artery.

The outcome of patients with acute myocardial infarction ineligible for thrombolytic therapy. Israeli Thrombolytic Survey Group.

PURPOSE: The aim of this study was to determine the proportion of patients with acute myocardial infarction (AMI) excluded from thrombolytic therapy on a national basis and to evaluate the prognosis of these patients by reasons of ineligibility and according to the alternative therapies that they received during hospitalization. PATIENTS AND METHODS: During a national survey, 1,014 consecutive patients with AMI were hospitalized in all the 25 coronary care units operating in Israel. RESULTS: Three hundred and eighty-three patients (38%) were treated with a thrombolytic agent and included in the GUSTO study. Ineligible patients for GUSTO were treated: (1) without any reperfusion therapy (n = 449), (2) by mechanical revascularization (n = 97), or (3) given 1.5 million units of streptokinase (n = 85) outside of the GUSTO protocol. The inhospital and 1-year post-discharge mortality rates were 6% and 2% in patients included in the GUSTO study; 6% and 5% in those mechanically reperfused; 15% and 10% in those treated with thromoblysis despite ineligibility for the GUSTO trial, and 15% and 13% among patients not treated with any reperfusion therapy. CONCLUSIONS: Ineligibility for thrombolysis among patients with AMI remains high. Patients ineligible for thrombolysis according to the GUSTO criteria, but nevertheless treated with a thrombolytic agent were exposed to an increased risk.

Late effects of dose fractionation on the mechanical properties of breast skin following post-lumpectomy radiotherapy.

PURPOSE: Late radiation-induced skin effects were studied in a multicenter project using our new sensitive noninvasive viscoelasticity skin analyzer (VESA). METHODS AND MATERIALS: Skin viscoelasticity and anisotropy were examined quantitatively in symmetric areas of both breasts in healthy women and in 110 breast cancer patients who underwent lumpectomy and radiotherapy. These parameters were evaluated by the VESA measurement of the speed of elastic wave propagation in the skin; higher VESA readings correspond to higher skin stiffness. Effect of radiation was estimated by comparison of the data recorded in the irradiated versus nonirradiated breast of the same patient. RESULTS: Skin viscoelasticity and anisotropy were similar in contralateral areas of the breasts in healthy controls as well as in the nonirradiated breasts of the patients. With age, skin viscoelasticity decreased and anisotropy increased similarly in both breasts. Radiotherapy, by a total radiation dose in the range of 45-50 Gy given with 1.8 Gy/fraction (fx) resulted in a similar minor, but still statistically significant, increase of skin stiffness relative to control. The effect was more pronounced when a dose of 50 Gy was given in a higher dose/fraction of 2.5 Gy. CONCLUSION: We found that the increase in dose of radiation per fraction had much more impact on the development of late skin effects than elevation in the total dose given.

Transradial approach for coronary angiography and angioplasty.

The transradial approach has currently been advocated as an alternative catheterization method for coronary angiography and angioplasty, due to the recent miniaturization of angioplasty equipment. The purpose of this study was to assess the practical clinical applicability of this method. From June to November 1994, 100 patients underwent coronary angiography and angioplasty with the transradial approach. Their mean age was 66.6 +/- 11.2 years, and 79 were men. In 4, radial puncture was not successful, and in 3, femoral access was necessary to complete the procedure. Coronary angioplasty was performed in 63 patients (76 lesions) with angiographic success (per lesion) of 96%. In 5 patients, a stent was successfully implanted. All patients were ambulatory on the day after the angioplasty procedure. In 98% of the patients, the introducer was taken out 1 to 4 hours after the procedure by local compression using a special custom-made device. No patient required blood transfusion. Major complications occurred in 2 patients; both had a cerebrovascular accident (1 probably not procedure-related), and both recovered. A radial pulse was palpated in 91 of the patients before discharge, and in 6 others, adequate flow could be heard with Doppler. In 2 patients, radial flow was restored within several weeks. None of the patients suffered from ischemia of the hand. Two patients had a small pseudoaneurysm successfully treated by local compression. Thus, coronary angioplasty can be performed safely using the transradial approach with relatively few vascular complications and with better patient comfort. However, the procedure is more time-consuming initially compared with the transfemoral approach due to a learning curve regarding equipment selection and catheter manipulation.

Experience with the AVE Micro stent in native coronary arteries.

Experience with implantation of 62 AVE Micro stents is described. Stents were quickly and successfully deployed in 62 of 63 attempts (98.4%), in tortuous coronary vessels, through proximally deployed stents, and under conditions of hemodynamic instability. It is therefore a very attractive choice to treat difficult anatomy during urgent situations.

Angiographic findings in the coronary arteries after thrombolysis in acute myocardial infarction.

The angiographic appearance of the coronary arteries was examined in 308 patients with acute myocardial infarction (AMI) who received high-dose intravenous thrombolytic therapy. Coronary angiography was performed on day 7 after admission to the hospital. Patients had an average of 2.4 discrete arterial narrowings or obstructions. The narrowings were proximal and related to bifurcations. Four fifths of the culprit arteries were patient; 104 (34%) had a ruptured plaque, 22 (7%) had an ulcerated plaque, and in 190 (62%) the lesions were eccentric. Patients differed from a comparable, previously studied, control series of 302 patients with chronic stable angina pectoris who had more extensive disease. They had 5.7 narrowings/patient, also located proximally and at bifurcations, but more widely distributed in the coronary tree. Patients with AMI who are suitable for thrombolysis have a unique coronary angiographic picture. The data confirm that AMI is caused by sudden rupture of a localized atheromatous plaque that initiates an obstructive thrombotic cascade.